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Markers of Sensitivity and Resistance to EGFR Inhibitors in Colorectal Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Jose G. Monzon, Janet E. Dancey
Less common genetic alterations that may activate AKT signaling and substitute for PIK3CA mutations include amplification of insulin receptor substrate 2 (IRS2), loss of PTEN expression, or co-amplification of AKT and PAK4 [24]. The latter two alterations are downstream mediators of PI3K signaling, while IRS2 is an upstream activator of PI3K. Of these alterations, the best characterized is the inactivation of the tumor suppressor gene PTEN, which encodes a phosphatase that dephosphorylates a lipid second messenger, phosphatidyllinositol (3,4,5) triphosphate (PIP3) to phosphatidylinositol (4,5) biphosphate (PIP2). PIP3 is the primary product of PI3K activity and its production antagonizes PI3K function and activates downstream signaling components, most notably the protein kinase AKT. Hence, the dephosphorylation of PIP3 is important because it results in the inhibition of the AKT signaling pathway. Loss of PTEN activity and subsequent loss of inhibition of AKT signaling is sufficient to cause a cancer phenotype by increasing cellular proliferation and reducing cell death. The PTEN gene may be inactivated via somatic mutations, allelic losses, and epigenetic hypermethylation [27–29].
Pediatric Central Nervous System Tumors as Phenotypic Manifestation of Cancer Predisposition Syndromes
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Giorgio Perilongo, Irene Toldo, Stefano Sartori
Dysplastic cerebellar gangliocytoma is a benign cerebellar neoplasm typically arising in young adults, rarely in children.74 This exquisitely rare pediatric neoplasm is usually seen in patients with Cowden syndrome or multiple hamartoma syndrome. Cowden syndrome is an autosomal-dominant inherited condition characterized by the presence of multiple papillomatous lesions, and multiple hamartomas which predispose affected patients to a high risk of developing follicular thyroid, breast, and endometrial cancers. Macrocephaly is considered potential clinical stigmata of Cowden syndrome. It has been linked to a germline mutation of the PTEN gene located at the 10q23 locus. The PTEN gene product is a negative regulator in the phosphatidylinositol-3-kinase protein kinase (PI3K-AKT) which targets the rapamycin (mTOR) signaling pathway.74,75
Cowden Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Among seven variants identified to date, CS1 accounts for 80% of clinical cases and shares with BRRS, PTEN-related Proteus syndrome, and Proteus-like syndrome in having PTEN mutations, which together are referred to as PTEN hamartoma tumor syndrome. The PTEN gene encodes a phosphatase that dephosphorylates the 3 position of phosphoinositide and thereby negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival. Mutations in the PTEN gene compromise its protein's function, leading to overproliferation of cells, hamartomatous growths, and predisposition to other cancers.
Extensive genomic analysis in patients with KRAS-mutated solid tumors shows high frequencies of concurrent alterations and potential targets but has limited clinical impact
Published in Acta Oncologica, 2022
Ida Christine Jacobsen, Iben Spanggaard, Martin Højgaard, Laïla Belcaid, Camilla Qvortrup, Christina Westmose Yde, Ane Yde Schmidt, Finn Cilius Nielsen, Gro Linno Willemoe, Mikkel Seidelin Dam, Ulrik Lassen, Kristoffer Staal Rohrberg
All reports were evaluated for co-alterations and actionability by board certified clinical oncologists at the Phase 1 Unit and were then recorded in REDCap. The recorded genomic alterations comprised all: (I) cancer-associated mutations (classified as either variant of unknown significance (VUS) or pathogenic) incl. high Tumor Mutational Burden (TMB) defined as >10 mut/Mb as defined by the Center for Genomic Medicine, corresponding to approx. 300 mutations (not exclusively missense mutations included) [19]; (II) fusions; (III) amplifications; (IV) biallelic deletions; (V) homologous recombination deficiency (HRD) [20]; and (VI) high expression of CEACAM5. All other expression findings, loss of heterozygosity (LOH), and deletions were not recorded due to potential inconsistency over time and low possibility of targetability. However, we included the PTEN gene if deletion and/or LOH occurred concomitantly with a mutation, corresponding to PTEN loss (biallelic deletion). In the case of multiple genomic reports showing alterations co-occurring with a KRAS mutation in the same patient, all alterations (I–VI) were recorded, but the same alteration would only be recorded once to prevent duplicate entries.
miR-92a promotes proliferation and inhibits apoptosis of prostate cancer cells through the PTEN/Akt signaling pathway
Published in Libyan Journal of Medicine, 2021
Zheng Yanshen, Yang Lifen, Wu Xilian, Dong Zhong, Mai Huihong
The deletion of phosphatase and tensin homologue gene (PTEN) on human chromosome 10 was first identified as a tumor suppressor in 1997 and later confirmed in following years [16]. PTEN, because of its demonstrated phosphatase activity, can hydrolyze PIP3 to generate PIP2, which intervenes the PI3K/Akt signaling pathway [17,18]. PI3K mediates the reversal of PIP2 to generate PIP3 and thereby activate the activity of a series of downstream signaling molecules, such as the phosphorylation of Akt. Enrinched p-Akt has been proven to promote cell survival, proliferation, growth, and differentiation, and to inhibit apoptosis and promote tumor tissue angiogenesis [19]. Many literature have reported that PTEN gene loses its cancer suppression ability due to genetic mutations in tumors, including PCa. Absence of PTEN fails to inhibit PI3K/Akt signaling pathway, resulting in its increased activity, thus exerting carcinogenic effect [20]. Recently, it has also been reported that miR-92a promotes colorectal cancer cell metastasis through PTEN-mediated PI3K/AKT pathway [21]; it enhances the metastatic potential of lung cancer cells by targeting PTEN-mediated AKT pathway [22]. Therefore, we hypothesize that miR-92a may also affect the biological function of PCa cells through the PTEN/Akt signaling pathway, and this study will investigate this hypothesis to provide new ideas for the treatment of PCa.
Association of PIK3CA mutation and PTEN loss with expression of CD274 (PD-L1) in colorectal carcinoma
Published in OncoImmunology, 2021
Tomotaka Ugai, Melissa Zhao, Takashi Shimizu, Naohiko Akimoto, Shanshan Shi, Yasutoshi Takashima, Rong Zhong, Mai Chan Lau, Koichiro Haruki, Kota Arima, Kenji Fujiyoshi, Benjamin Langworthy, Yohei Masugi, Annacarolina da Silva, Katsuhiko Nosho, Yoshifumi Baba, Mingyang Song, Andrew T. Chan, Molin Wang, Jeffrey A. Meyerhardt, Marios Giannakis, Juha P. Väyrynen, Jonathan A. Nowak, Shuji Ogino
We acknowledge several limitations in this study. First, our study examined PIK3CA mutation and PTEN loss but did not examine somatic mutations in PTEN gene.66 However, the majority of cases with PTEN loss in colorectal cancer have been attributed to epigenetic causes such as hypermethylation,30 and immunohistochemistry used in this study is able to detect loss of protein expression irrespective of cause. Second, measurement errors may exist in molecular tissue data. However, such errors would likely be nearly randomly distributed and drive our results toward the null hypothesis. Third, our study was an observational, cross-sectional analysis, and further in vivo and in vitro experimental studies are needed to elucidate the mechanisms underlying our findings. Lastly, in this study, separate single-color immunohistochemistry assays did not allow the examination of co-expression patterns of PTEN and CD274 at the single cell level. Therefore, multiplex immunohistochemistry or immunofluorescence assays should be considered in future studies.